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 Blood, 1 December 2008, Vol. 112, No. 12, pp. 4655-4664.
Prepublished online as a Blood First Edition Paper on August 6, 2008; DOI 10.1182/blood-2008-02-139105.

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NEOPLASIA

Leukemic challenge unmasks a requirement for PI3K{delta} in NK cell–mediated tumor surveillance

Eva Zebedin1, Olivia Simma1, Christian Schuster1, Eva Maria Putz1, Sabine Fajmann1, Wolfgang Warsch1, Eva Eckelhart1, Dagmar Stoiber2, Eva Weisz2, Johannes A. Schmid2, Winfried F. Pickl3, Christian Baumgartner4, Peter Valent4, Roland P. Piekorz5, Michael Freissmuth1, and Veronika Sexl1

1 Institute of Pharmacology, Medical University of Vienna (MUW), Vienna, Austria; 2 Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria; 3 Institute of Internal Medicine I, MUW, Vienna, Austria; 4 Institute of Immunology, MUW, Vienna, Austria; and 5 Institute of Biochemistry and Molecular Biology II, Heinrich-Heine-University, Düsseldorf, Germany

Specific inhibitors of PI3K isoforms are currently evaluated for their therapeutic potential in leukemia. We found that BCR/ABL+ human leukemic cells express PI3K{delta} and therefore explored its impact on leukemia development. Using PI3K{delta}-deficient mice, we define a dual role of PI3K{delta} in leukemia. We observed a growth-promoting effect in tumor cells and an essential function in natural killer (NK) cell–mediated tumor surveillance: Abelson-transformed PI3K{delta}-deficient cells induced leukemia in RAG2-deficient mice with an increased latency, indicating that PI3K{delta} accelerated leukemia progression in vivo. However, the absence of PI3K{delta} also affected NK cell–mediated tumor surveillance. PI3K{delta}-deficient NK cells failed to lyse a large variety of target cells because of defective degranulation, as also documented by capacitance recordings. Accordingly, transplanted leukemic cells killed PI3K{delta}-deficient animals more rapidly. As a net effect, no difference in disease latency in vivo was detected if both leukemic cells and NK cells lack PI3K{delta}. Other tumor models confirmed that PI3K{delta}-deficient mice succumbed more rapidly when challenged with T- or B-lymphoid leukemic or B16 melanoma cells. Thus, the action of PI3K{delta} in the NK compartment is as relevant to survival of the mice as the delayed tumor progression. This dual function must be taken into account when using PI3K{delta} inhibitors as antileukemic agents in clinical trials.


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